Introduction
Chronic rhinosinusitis (CRS) impairs quality of life as well as work productivity (1) and has a high socioeconomic burden (1). In the Global Allergy and Asthma European Network (GA2LEN) European multicentre study involving 56 000 adult subjects, a prevalence rate of CRS of 10.9% was determined with a range from 6.9 to 27.1% in Europe (2). The CRS comprised heterogeneous diseases and was differentiated by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS 2020) in phenotypes with and without nasal polyps (CRSwNP/ CRSsNP) (3). Subtypes are non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD), cystic fibrosis, and the allergic fungal rhinosinusitis (3). CRS is associated with asthma (4). Evidence-based therapies consist of nasal corticosteroids in CRSsNP and nasal/oral corticosteroids in CRSwNP (3). In cases without improvement under conservative treatment, surgery of nasal sinuses is recommended according to the EPOS 2020 criteria (3). Despite the evidence-based therapy options, an acceptable level of disease control is still not reached in a high proportion of patients (5). There is a particularly high risk of disease recurrence following nasal sinus surgery for patients with CRSwNP (5, 6). New therapy concepts developed for severe CRSwNP consist of modified nasal sinus surgeries as reboot operations that aim to entirely remove all nasal sinus mucosa and allow healthy reepithelialization from the preserved nasal mucosa (7). Biological treatment options are gaining evidence as an efficient therapy (8-10) in CRSwNP. The CRS can be characterized by a wide range of factors, such as histopathological findings, specific inflammatory and T-cell patterns, tissue remodeling parameters, the concentration of eicosanoids, and IgE production (11). The current phenotyping in CRSwNP and CRSsNP might not sufficiently reflect pathophysiological processes within the CRS disease. Therefore, elucidation of the pathomechanisms underlying CRS, with the aim to develop specific and personalized therapy strategies, might improve specific therapy options. First results of the GA2LEN Sinusitis Cohort study in the framework of the European FP6 research initiative have already been published by Tomassen et al. (12). This multicenter case-controlled study focused on the analysis of immune markers of nasal sinus tissues from CRS patients. This second cluster analysis followed the first analysis, and the CRS patients were assigned to groups CRSsNP, CRSwNP, and asthma comorbidity. The study included parameters regarding tissue remodeling, proinflammatory cytokines, cytokines of type 1-, type 2 inflammation and Th17 lymphocyte pattern, eosinophil and neutrophil activation markers as well as Staphylococcus aureus enterotoxin-specific IgE (SE-IgE). Based on the detected IL-5 concentrations, CRS was divided into ten clusters with low/ undetectable IL-5 and moderate or high concentrations of IL-5. The group of IL-5-negative clusters represented mainly the CRSsNP phenotype, while with increasing IL-5 levels, the proportion of the CRSwNP phenotype raised to 100 %, with high IL-5 and positive SE-IgE. The asthma prevalence increased with the elevation of IL-5 levels and the presence of SE-IgE (12), but the presence and concentration of chemokines were not analyzed so far.
Chemokines are small peptides (8-14 kDa) that induce chemotactic activity in chemokine-receptor-positive cells. Chemokines influence the activation status of the target cells and selectively regulate the directed migration of specific inflammatory cells. They are also involved in cell recruitment, inflammation, angiogenesis, type 1/ type 2 inflammation, wound healing, and lymphoid trafficking (13). The classification of chemokines is based on the positioning of the first two cysteine residues. Following chemokine families were defined: CXC, CC, C, and CX3C (14). These families differ in function, e.g., CC chemokines activate monocytes, basophils, eosinophils, T-lymphocytes, and natural killer cells, whereas CXC chemokines stimulate mainly neutrophils (15).
The general aim of the present study was analogous to previously published GA2LEN study ”Chronic rhinosinusitis and nasal polyposis cohort study”, aiming to match the immune patterns with the phenotypes CRSwNP, CRSsNP, and comorbid asthma.
The primary aim of this substudy was to characterize chemokine patterns in the tissue of CRS patients in relation to the levels of the Th2 related parameter IL-5 primarily, and subsequently assign them to the phenotypes CRSwNP and CRSsNP and associated comorbidities asthma and N-ERD. We analyzed the concentration of the CC-chemokines TARC/CCL17, PARC/CCL18, eotaxin/CCL11, MCP-3/CCL7, MIP-1α /CCL3, IP-10 /CXCL10, and the CXC chemokine ENA-78/CCL5.
The secondary aim of the study was to examine the influences of the additional parameters MPO, IL-17 (neutrophilic), IL-22, TNF-α, and IFN-γ (Th1-associated) on chemokine patterns. The use of biologics for the therapy of severe CRS with nasal polyps expands increasingly. Therefore, improving the understanding of pathomechanisms behind CRS, and performing systematic characterization of CRS endotypes could lead to the discovery of new biomarkers, advancing the choice of specific biologics for the treatment of uncontrolled severe CRSwNP.